CD8 T cells play a critical role in controlling intracellular pathogens and preventing the outgrowth of tumorigenic cells;however, more prolonged and persistent infections can become established. Our laboratory, as well as others, have documented that the inability to rapidly clear certain viral infections is associated with the development of defective CD8 T cell responses. Under these conditions a stepwise and progressive functional inactivation of antigen-specific CD8 T cells ensues as the responding cells fail to phenotypically mature into memory T cells. If the infection persists then this may culminate in the physical deletion of the CD8 T cells. Encouraging reports suggest that if high viral loads can be reduced, within a sufficient timeframe, then at least a partial restoration of CD8 T cell effector activities can occur and more typical memory T cells may emerge. Determining how to promote, sustain, and potentially reactivate robust sets of anti-viral CD8 T cells is, therefore, likely to enhance immunity to persistent viral infections. Nevertheless, it is ill-defined whether the progressive diminution of anti-viral CD8 T cell effector activities is developmentally programmed or solely driven by antigen abundance, and it is also not known if certain subsets of CD8 T cells are more resistant to functional inactivation during the early stages of infection. Conversely, it is unclear whether all subsets of functionally impaired anti-viral CD8 T cells exhibit a similar capability of regaining effector activities and whether the protective efficacy of these functionally reactivated CD8 T cells matches that of normal, resting memory T cells. We will investigate these issues by addressing the hypothesis that antigen load, in conjunction with the cytokine milieu, serves as a rheostatic regulator of the functional quality and maturation state of anti-viral CD8 T cells. Our specific aims are: (1) To determine the susceptibility of optimally primed CD8 T cells to functional exhaustion;(2) To determine the impact of antigen withdrawal and cytokine milieu on the phenotypic and functional properties of sub-optimal CD8 T cell subsets;(3) To determine whether bona fide memory CD8 T cells develop following the resolution of prolonged viral infections. More protracted and chronic infections are difficult to eradicate and are of particular public health concern. The findings of these studies are likely to provide new information regarding how anti-viral CD8 T cell responses can be fine-tuned to better combat persistent infections, and are relevant to our ability to devise strategies to control potential emerging pathogens.